We wanted to clarify some of the points that were brought up in your discussion:

Our work started with the observation that human cytomegalovirus infection induces the expression of m6A machinery. While we still don’t know what is the exact factor that drives this upregulation, we know that infection with UV-inactivated virus does not induce the expression of m6A machinery (shown in Ian Mohr’s paper and in our unpublished data). This implies that the induction is driven by a viral gene/s that are actively transcribed following infection.

As you discussed, we show that depletion of m6A machinery leads to increased interferon transcript stability and increase in interferon stimulated-gene expression. However, this happens also following treatments that do not induce the m6A machinery (infection with a UV-inactivated virus or, in Ian Mohr’s study, by transfection of dsDNA). This means that the regulation of interferon transcript by its methylation occurs regardless of the upregulation of the m6A machinery, and it is therefore an intrinsic property of IFN, probably designated to limit the duration of the antiviral response.

Furthermore, the benefits of the induction of m6A “writers” and “readers” for the virus are yet to be completely understood. The available m6A mapping methodologies are not quantitative, so we still don’t know how this upregulation of the m6A machinery affects the stoichiometry and combinatory of interferon transcript methylation and whether this further enhances the destabilization of IFN transcripts. Although our results show that the increased interferon response in cells depleted of m6A machinery is the main reason for the inhibition in viral propagation in these cells, the induction of m6A machinery could possibly serve the virus in additional ways.

I hope this clarified some issues.

Trudy writes:

Dear TWiVers,

Brisbane is located on the East Coast of Australia, right in the middle, or at the country’s equator. To address Dickson’s comment, while it is most definitely below Cairns, it is not ANYWHERE NEAR Cairns. It actually takes almost 20 hours to get from Brisbane to Cairns by car. It takes about that long to get from any one major city to the other in Australia. I lived in Brisbane for 5 years and made it to Sydney, Canberra, Melbourne, and Adelaide, but unfortunately not to Cairns. I have attached a map for context.

Kind Regards,

Trudy.

Jens writes:

Dear TWiV Team,

Just catching up on TWiV, now listening to “Recurring Threads”. Two comments:

“Makona versus Ebola”. Maybe the following opposition helps:

Family: Canidae Filoviridae

Genus: CanisEbolavirus

Species: CanisfamiliarisZaire ebolavirus

Animal: dog Virus: Ebola virus

Breed: Siberian Husky Variant: Makona

Individual: Spot Isolate: C05

Btw, “Mayinga” is an isolate name of the “Yambuku” variant of Ebola virus.

Species versus things. What a species “is” has not been decided and even Darwin carefully shied away from defining it. However, notably he had no problem describing and defining animals, which are the members of species. I attached two fun paper for you guys to read about the issue – you will see that many people in zoology and botany also consider species concepts rather than real things (and many oppose that view).

The way I see it: a species “is” what you see when you close your eyes and you “see” Tyrannosaurus rex. The image comes from all the knowledge (right or wrong) you have about all the individual animal specimens that are very very closely related and this knowledge is meshed together as some kind of an average. For instance, many museum dinosaur skeletons are mosaics of bones found at different places, i.e. they do not actual truly represent a single animal. Likewise there may be deductions on muscle mass from currently living reptiles and artists’ renderings of skin color etc. etc. Obviously, the T. rex in your imagination does not exist (and also never existed) – hence the “species are not things idea”.

Translated to modern times: even if you sequence 1 million human genomes you will not know all the different variations that are permitted in a human genome to still result in a human. Hence even 1 million genomes are only an approximation of what a human genome “is” – and by extrapolation what a human “is”. Even if you sequence everybody living – you would have no idea about the traits of those who have lived or those who will live. Thus, the species “Homo sapiens” is again that image in your mind of what a human “is” based on all the averaged/overlaid knowledge we have on actual individual humans that one can actually study.

One more: imagine you find a single skeleton of a novel prehistoric primate and that primate has a cleft palate. If you base your species definition solely on this one skeleton, then the species definition would be “must have a cleft palate”. However, maybe the cleft palate is an aberration – which you will only know if you sample more and more specimens and adjust your species definition accordingly with every new found data point (likely the species definition will change to “mostly does not but may have cleft palates”). That again clarifies that a species cannot be studied – as it is a concept constantly in flux.

Last and best one: if I ask you to imagine the species “Homo sapiens” and you see a man in your mind – then you are sexist even if the very man you think about actually exists. The species is more than just males, again emphasizing that averaging point I made above: the human species is both male and female and everything in between at the same time (and hence can hardly be studied).

But again, that is just how I wrap my head around all of this. Please also see the attached article I co-write many moons ago on this subject, which contains this wonderful quote from Richard Dawkins:

‘‘[t]he rabbits that we see are wan shadows of the perfect ‘idea’ of rabbit, the ideal, essential Platonic rabbit, hanging somewhere out in conceptual space… Flesh-and-blood rabbits

may vary, but their variations are always to be seen as flawed deviations from the ideal essence of rabbit”.

That ideal essence is the species Oryctolagus cuniculus.

Best,

Jens

PS:

The plural of “taxon” is “taxa”…

Anne writes:

Please share this Kickstarter project for an updated edition of the board game Pathogenesis with your listeners. I’m pretty sure I heard about the game on one of your podcasts. The second edition of the game has now been listed on Kickstarter, and I imagine many of your listeners might be interested in having the game, or updating their first editions versions with the STD expansion kit.

I don’t know how long Kickstarters run, so getting the word out quickly to help bring the second edition to life would no doubt be helpful.

I’m not affiliated with the project – I just think it’s a great idea to help students learn the complex subject of immunology, including me!

Regards from a loyal listener who appreciates all that you and your teams do to bring more science to the masses,

Anne

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